The cuprizone animal model: new insights into an old story
Abstract
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system and represents the most common neurological disorder in young adults in the Western hemisphere. There are several well-characterized experimental animal models that allow studying potential mechanisms of MS pathology. While experimental allergic encephalomyelitis is one of the most frequently used models to investigate MS pathology and therapeutic interventions, the cuprizone model reflects a toxic experimental model. Cuprizone-induced demyelination in animals is accepted for studying MS-related lesions and is characterized by degeneration of oligodendrocytes rather than by a direct attack on the myelin sheet. The present article reviews recent data concerning the cuprizone model and its relevance for MS. Particular focus is given to the concordance and difference between human MS patterns (types I-IV lesions) and cuprizone-induced histopathology, including a detailed description of the sensitive brain regions extending the observations to different white and grey matter structures. Similarities between pattern III lesions and cuprizone-induced demyelination and dissimilarities, such as inflamed blood vessels or the presence of CD3+ T cells, are outlined. We also aim to distinguish acute and chronic demyelination under cuprizone including processes such as spontaneous remyelination during acute demyelination. Finally, we point at strain and gender differences in t…
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The cuprizone neurotoxicity animal model is widely used in MS research.
“The cuprizone neurotoxicity animal model is widely used in MS research [3].”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [3]
Early after cuprizone initiation and in the context of minimal inflammation, changes in myelin composition and/or lipid polarity are detected well in advance of oligodendrocyte cell body damage, giving weight to the idea that cuprizone may have direct, albeit subtle, effects on myelin.
“Early after cuprizone initiation and in the context of minimal inflammation, changes in myelin composition and/or lipid polarity have been detected well in advance of oligodendrocyte cell body damage giving weight to the idea that cuprizone may have direct, albeit subtle, effects on myelin [79, 98, 99]”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [79]
Astrocytes and microglia collaborate through the release of cytokines, chemokines, and other factors to drive demyelination; preventing the release of specific cytokines or chemokines, restricting astrocyte reactivity, or ablating microglia all reduce cuprizone-induced demyelination.
“Astrocytes and microglia collaborate through the release of cytokines, chemokines, and other, yet to be identified factors, to drive demyelination [79, 107], preventing the release of specific cytokines or chemokines, restricting astrocyte reactivity, or ablating microglia all reduce cuprizone-induced demyelination [107, 181, 189, 243].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [79]
The cuprizone model is a toxin-induced demyelination model.
“In the following chapter we will briefly introduce the cuprizone model, a toxin-induced demyelination model [21,22].”
From The Cuprizone Model: Dos and Do Nots (2020) · cites this paper as [21]
Oral intoxication with the copper-chelator cuprizone induces oligodendrocyte apoptosis within a few days, followed by activation of innate immune cells in the brain, astrocytes and microglia, and finally demyelination of distinct white and grey matter brain areas.
“Oral intoxication with the copper-chelator cuprizone induces oligodendrocyte apoptosis within a few days, which is closely followed by the activation of the innate immune cells in the brain, i.e., astrocytes and microglia, finally leading to demyelination of distinct white and grey matter brain areas.”
From The Cuprizone Model: Dos and Do Nots (2020) · cites this paper as [21]
Cites
Myelin Impairs CNS Remyelination by Inhibiting Oligodendrocyte Precursor Cell Differentiation
Kotter, M. R., Li, W.-W., Zhao, C., & Franklin, R. J. M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2615-05.2006 · Cited by 768 · see citing works
Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation
Back, S. A., Tuohy, T. M. F., Chen, H., Wallingford, N., Craig, A., Struve, J., Luo, N. L., Banine, F., Liu, Y., Chang, A., et al. (2005) · Nature Medicine · doi:10.1038/nm1279 · Cited by 612 · see citing works
Treatment of multiple sclerosis with the pregnancy hormone estriol
Sicotte, N. L., Liva, S. M., Klutch, R., Pfeiffer, P., Bouvier, S., Odesa, S., Wu, T. C. J., & Voskuhl, R. R. (2002) · Annals of Neurology · doi:10.1002/ana.10301 · Cited by 435 · see citing works
Baer, A. S., Syed, Y. A., Kang, S. U., Mitteregger, D., Vig, R., ffrench-Constant, C., Franklin, R. J. M., Altmann, F., Lubec, G., & Kotter, M. R. (2009) · Brain · doi:10.1093/brain/awn334 · Cited by 211 · see citing works
Murtie, J. C., Zhou, Y.-X., Le, T. Q., Vana, A. C., & Armstrong, R. C. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.12.006 · Cited by 157 · see citing works
Platelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter
Vana, A. C., Flint, N. C., Harwood, N. E., Le, T. Q., Fruttiger, M., & Armstrong, R. C. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181587d46 · Cited by 101 · see citing works
Taylor, L. C., Gilmore, W., & Matsushima, G. K. (2009) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00230.x · Cited by 84 · cited 3× · see citing works
“Gender-based differences or gender-related hormonal influences are well accepted to influence remyelination efficacy [1, 90].”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Oligodendrocytes in development, myelin generation and beyond
Kuhn, S., Gritti, L., Crooks, D., & Dombrowski, Y. (2019) · Cells · doi:10.3390/cells8111424 · Cited by 625 · see citing works
Praet, J., Guglielmetti, C., Berneman, Z., Van der Linden, A., & Ponsaerts, P. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.10.004 · Cited by 435 · see citing works
Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned
Gudi, V., Gingele, S., Skripuletz, T., & Stangel, M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00073 · Cited by 375 · see citing works
“…demyelination primarily induced by oligodendroglial damage linked to mitochondrial dysfunctions, as seen in MS pattern III and IV lesions, is mimicked by the cuprizone model (Torkildsen et al., 2008; Kipp et al., 2009; Liu et al., 2010; Veto et al., 2010; Acs and Komoly, 2012; Kang et al., 2012).”
BackgroundInfluentialZirngibl, M., Assinck, P., Sizov, A., Caprariello, A. V., & Plemel, J. R. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00538-8 · Cited by 233 · see citing works
The Cuprizone Model: Dos and Do Nots
Zhan, J., Mann, T., Joost, S., Behrangi, N., Frank, M., & Kipp, M. (2020) · Cells · doi:10.3390/cells9040843 · Cited by 171 · see citing works
“In the following chapter we will briefly introduce the cuprizone model, a toxin-induced demyelination model [21,22].”
BackgroundSelf-citationCXCL10 Triggers Early Microglial Activation in the Cuprizone Model
Clarner, T., Janssen, K., Nellessen, L., Stangel, M., Skripuletz, T., Krauspe, B., Hess, F.-M., Denecke, B., Beutner, C., Linnartz-Gerlach, B., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1401459 · Cited by 150 · see citing works
Self-citationAnti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases
Diz-Chaves, Y., Mastoor, Z., Spuch, C., González-Matías, L. C., & Mallo, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179583 · Cited by 148 · see citing works
El-Etr, M., Rame, M., Boucher, C., Ghoumari, A. M., Kumar, N., Liere, P., Pianos, A., Schumacher, M., & Sitruk-Ware, R. (2015) · Glia · doi:10.1002/glia.22736 · Cited by 116 · see citing works
Plemel, J. R., Caprariello, A. V., Keough, M. B., Henry, T. J., Tsutsui, S., Chu, T. H., Schenk, G. J., Klaver, R., Yong, V. W., & Stys, P. K. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201602028 · Cited by 97 · see citing works
Falangola, M. F., Guilfoyle, D. N., Tabesh, A., Hui, E. S., Nie, X., Jensen, J. H., Gerum, S. V., Hu, C., LaFrancois, J., Collins, H. R., et al. (2014) · NMR in Biomedicine · doi:10.1002/nbm.3140 · Cited by 96 · see citing works
Zhang, J., Jones, M. V., McMahon, M. T., Mori, S., & Calabresi, P. A. (2012) · Magnetic Resonance in Medicine · doi:10.1002/mrm.23032 · Cited by 88 · see citing works
Neurodegeneration Triggers Peripheral Immune Cell Recruitment into the Forebrain
Scheld, M., Rüther, B. J., Große-Veldmann, R., Ohl, K., Tenbrock, K., Dreymüller, D., Fallier-Becker, P., Zendedel, A., Beyer, C., Clarner, T., et al. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2456-15.2016 · Cited by 82 · see citing works
Self-citationSpatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model
Tagge, I., O’Connor, A., Chaudhary, P., Pollaro, J., Berlow, Y., Chalupsky, M., Bourdette, D., Woltjer, R., Johnson, M., & Rooney, W. (2016) · PLOS ONE · doi:10.1371/journal.pone.0152480 · Cited by 81 · see citing works
An overall view of the most common experimental models for multiple sclerosis
Dedoni, S., Scherma, M., Camoglio, C., Siddi, C., Dazzi, L., Puliga, R., Frau, J., Cocco, E., & Fadda, P. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106230 · Cited by 79 · see citing works
IL-17-Induced Act1-Mediated Signaling Is Critical for Cuprizone-Induced Demyelination
Kang, Z., Liu, L., Spangler, R., Spear, C., Wang, C., Gulen, M. F., Veenstra, M., Ouyang, W., Ransohoff, R. M., & Li, X. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0841-12.2012 · Cited by 78 · see citing works
Guglielmetti, C., Le Blon, D., Santermans, E., Salas-Perdomo, A., Daans, J., De Vocht, N., Shah, D., Hoornaert, C., Praet, J., Peerlings, J., et al. (2016) · Glia · doi:10.1002/glia.23053 · Cited by 76 · see citing works
Butti, E., Bacigaluppi, M., Chaabane, L., Ruffini, F., Brambilla, E., Berera, G., Montonati, C., Quattrini, A., & Martino, G. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0227-18.2019 · Cited by 67 · see citing works
White matter biomarkers from fast protocols using axially symmetric diffusion kurtosis imaging
Hansen, B., Khan, A. R., Shemesh, N., Lund, T. E., Sangill, R., Eskildsen, S. F., Østergaard, L., & Jespersen, S. N. (2017) · NMR in Biomedicine · doi:10.1002/nbm.3741 · Cited by 46 · see citing works
Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models
Nack, A., Brendel, M., Nedelcu, J., Daerr, M., Nyamoya, S., Beyer, C., Focke, C., Deussing, M., Hoornaert, C., Ponsaerts, P., et al. (2019) · Cells · doi:10.3390/cells8020094 · Cited by 43 · see citing works
Self-citationBrain lipid binding protein (FABP7) as modulator of astrocyte function
KIPP, M., CLARNER, T., GINGELE, S., POTT, F., AMOR, S., VAN DER VALK, P., & BEYER, C. (2011) · Physiological Research · doi:10.33549/physiolres.932168 · Cited by 42 · see citing works
Self-citationStrain differences in cuprizone induced demyelination
Yu, Q., Hui, R., Park, J., Huang, Y., Kusnecov, A. W., Dreyfus, C. F., & Zhou, R. (2017) · Cell & Bioscience · doi:10.1186/s13578-017-0181-3 · Cited by 40 · see citing works
Animal models to investigate the effects of inflammation on remyelination in multiple sclerosis
Gharagozloo, M., Mace, J. W., & Calabresi, P. A. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.995477 · Cited by 38 · see citing works
Sen, M. K., Almuslehi, M. S. M., Gyengesi, E., Myers, S. J., Shortland, P. J., Mahns, D. A., & Coorssen, J. R. (2019) · Cells · doi:10.3390/cells8111314 · Cited by 35 · see citing works
Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis
Varga, E., Pandur, E., Abrahám, H., Horváth, A., Ács, P., Komoly, S., Miseta, A., & Sipos, K. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0578-5 · Cited by 27 · see citing works
Friesen, E., Hari, K., Sheft, M., Thiessen, J. D., & Martin, M. (2024) · Magnetic Resonance Materials in Physics, Biology and Medicine · doi:10.1007/s10334-024-01160-z · Cited by 7 · see citing works
- Authors
- Kipp, M., Clarner, T., Dang, J., Copray, S., & Beyer, C.
- Affiliations
- RWTH Aachen University (DE)
- University Medical Center Groningen (NL)
- Corresponding author
- Kipp, Markus
- Venue
- Acta Neuropathologica
- Published
- 2009-09-18
- Volume
- 118
- Issue
- 6
- Pages
- 723-736
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2058785790
- Cited by
- 481
- References
- 7
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 24 · 2023: 32 · 2022: 31 · 2021: 33 · 2020: 33 · 2019: 40 · 2018: 40 · 2017: 50 · 2016: 29 · 2015: 26 · 2014: 31 · 2013: 29 · 2012: 21
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Multiple Sclerosis Society
- RWTH Aachen University
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- cuprizone, multiple sclerosis, demyelination, oligodendrocyte degeneration, animal models, remyelination, strain differences, sex differences, growth factors, cytokines, leukemia inhibitory factor, insulin-like growth factor I
- MeSH terms
- Animals, Cuprizone, Disease Models, Animal, Multiple Sclerosis, Myelin Sheath
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